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Safety and Pharmacokinetic Study of HIV Prophylaxis Using Antiretroviral Intravaginal Rings in Healthy Women

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02431273
Recruitment Status : Completed
First Posted : May 1, 2015
Results First Posted : July 2, 2019
Last Update Posted : July 2, 2019
Sponsor:
Collaborators:
The University of Texas Medical Branch, Galveston
Oak Crest Institute of Science
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Auritec Pharmaceuticals

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Condition Human Immunodeficiency Virus (HIV) Prophylaxis
Interventions Drug: TDF IVR
Drug: TDF-FTC IVR
Drug: TDF-FTC-MVC IVR
Enrollment 10
Recruitment Details  
Pre-assignment Details  
Arm/Group Title TDF (Single IVR), TDF-FTC (Dual IVR), TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description

All subjects will be asked to wear TDF (Single) IVRs for 7 days.

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days.

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days.

Period Title: TDF (Single IVR)
Started 6
Completed [1] 6
Not Completed 0
[1]
All 6 participants that completed Period 1 (TDF IVR) screened for Period 2 (TDF-FTC IVR)
Period Title: TDF-FTC (Dual IVR)
Started 6
Completed [1] 6
Not Completed 0
[1]
2 of 6 participants that completed Period 2 (TDF-FTC IVR) screened for Period 3 (TDF-FTC-MVC IVR)
Period Title: TDF-FTC-MVC (Triple IVR)
Started 6
Completed [1] 6
Not Completed 0
[1]
2 participants that completed Periods 1 and 2, along with 4 new subjects participated in Period 3
Arm/Group Title All Study Participants
Hide Arm/Group Description

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

Overall Number of Baseline Participants 10
Hide Baseline Analysis Population Description
6 subjects were screened, entered, and completed Period 1: TDF-IVR (Single IVR). The 6 subjects then completed Period 2: TDF-FTC (Dual IVR). 4 of the 6 subjects dropped out afterward. 2 of the 6 original subjects, plus 4 new subjects entered Period 3: TDF-FTC-MVC (Triple IVR). Here, baseline data of all subjects are presented.
Age, Continuous   [1] 
Mean (Full Range)
Unit of measure:  Years
Period 1 and Period 2 Number Analyzed 6 participants
26
(24 to 35)
Period 3 Number Analyzed 6 participants
24.5
(21 to 41)
[1]
Measure Analysis Population Description:

6 subjects were screened, entered, and completed Period 1: TDF-IVR (Single IVR) and Period 2: TDF-FTC (Dual IVR).

2 of the 6 original subjects, plus 4 new subjects entered Period 3: TDF-FTC-MVC (Triple IVR). Total of 6 subjects were analyzed for each Period.

Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Female
10
 100.0%
Male
0
   0.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
Hispanic or Latino
4
  40.0%
Not Hispanic or Latino
6
  60.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
2
  20.0%
White
8
  80.0%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 10 participants
10
 100.0%
1.Primary Outcome
Title Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs)
Hide Description Number of Adverse Events (AEs) was recorded. Safety parameters were monitored for each IVR combination and the grading scale for each parameter followed the Female Genital Grading Table for Use in Microbicide Studies. AEs not included in that table were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014 (Grade 1 = mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Potentially Life-Threatening).
Time Frame Days 0-21 following insertion of each IVR.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 6
Measure Type: Number
Unit of Measure: participants
Pelvic Pain: Grade 1 4 1 4
Pelvic Pain: Grade 2 1 1 0
Vaginal Discharge: Grade 1 3 3 1
Metrorrhagia: Grade 1 1 0 2
Vulvovaginal Itching: Grade 1 3 0 1
Cervicovaginal Erythema: Grade 1 3 1 0
Diarrhea: Grade 1 1 0 0
Malaise: Grade 1 1 0 0
Odor: Grade 1 0 0 1
Nausea: Grade 1 0 0 1
Candida (monilial vulvovaginitis): Grade 2 0 0 1
2.Primary Outcome
Title Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Fluid (CVF)
Hide Description Drug concentrations [tenofovir (TFV), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in cervicovaginal fluids (CVF) for each IVR combination.
Time Frame Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 6
Median (Inter-Quartile Range)
Unit of Measure: ng/mg
tenofovir disoproxil fumarate
58.1
(43.9 to 97.4)
43.1
(31.0 to 65.0)
96.9
(14.5 to 137.1)
tenofovir
13.9
(6.2 to 19.3)
15.9
(7.1 to 20.0)
28.0
(24.3 to 31.9)
Total tenofovir
36.2
(31.3 to 60.6)
34.4
(26.9 to 48.7)
70.0
(59.2 to 80.6)
emtricitabine
NA [1] 
(NA to NA)
896
(367.0 to 1349.0)
838.5
(641.8 to 1171.2)
maraviroc
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
429.8
(253.2 to 626.2)
[1]
The IVR did not contain emtricitabine
[2]
The IVR did not contain maraviroc
3.Primary Outcome
Title Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Lavage (CVL)
Hide Description Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in cervicovaginal lavage (CVL) were evaluated for each IVR combination.
Time Frame Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 6
Median (Inter-Quartile Range)
Unit of Measure: ng/mL
tenofovir disoproxil fumarate
1,930
(1,040 to 2,290)
1,720
(1,028 to 3,429)
3,630
(2,310 to 15,700)
tenofovir
611
(242 to 2,440)
927
(315 to 1,253)
2,670
(1,668 to 4,175)
4.Primary Outcome
Title Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Vaginal Tissue
Hide Description Drug concentrations [tenofovir disoproxil fumarate (TDF), tenofovir (TFV), tenofovir diphosphate (TFV-DP), emtricitabine (FTC) and maraviroc (MVC)] in vaginal tissue (VT) were evaluated for each IVR combination.
Time Frame Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 6
Median (Inter-Quartile Range)
Unit of Measure: ng/mg
tenofovir
8.4
(4.7 to 11.2)
5.1
(0.8 to 10.1)
5.1
(3.3 to 9.7)
tenofovir diphosphate
303
(277 to 938)
289
(110 to 603)
301.9
(177.1 to 823.8)
emtricitabine
NA [1] 
(NA to NA)
23,950
(11,373 to 56,400)
104
(63.7 to 301.7)
maraviroc
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
141.8
(82.5 to 212)
[1]
The IVR did not contain emtricitabine
[2]
The IVR did not contain maraviroc
5.Primary Outcome
Title Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Plasma
Hide Description Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in plasma were evaluated for each IVR combination.
Time Frame Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 6
Median (Inter-Quartile Range)
Unit of Measure: ng/mL
tenofovir: Plasma
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
emtricitabine: Plasma
NA [2] 
(NA to NA)
0.95
(0.91 to 1.14)
1.02
(0.56 to 1.22)
maraviroc: Plasma
NA [3] 
(NA to NA)
NA [3] 
(NA to NA)
0.08
(0.05 to 0.14)
[1]
Data is below the lower limit of quantification
[2]
The IVR did not contain emtricitabine
[3]
The IVR did not contain maraviroc
6.Primary Outcome
Title Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Terminal Half-life
Hide Description Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in terminal half-life were evaluated for each IVR combination.
Time Frame Time points at which outcome measure was assessed are Day 7 (day of IVR removal) and daily up to 14 days.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 6
Median (Inter-Quartile Range)
Unit of Measure: Hour
tenofovir disoproxil fumarate: Terminal Half-life
11.8
(10.6 to 14.4)
14.2
(11.7 to 15.4)
18.3
(11.8 to 24.2)
tenofovir: Terminal Half-life
39.5
(30.0 to 58.1)
31.4
(25.9 to 36.2)
24.8
(24.4 to 31.9)
emtricitabine: Terminal Half-life
NA [1] 
(NA to NA)
19.1
(13.5 to 20.1)
17.0
(15.5 to 17.8)
maraviroc: Terminal Half-life
NA [2] 
(NA to NA)
NA [2] 
(NA to NA)
16.0
(15.8 to 18.3)
[1]
The IVR did not contain emtricitabine
[2]
The IVR did not contain maraviroc
7.Secondary Outcome
Title Acceptability of the IVRs
Hide Description Acceptability of the IVRs was assessed through reported willingness to use the IVR for 28 days in a real-world setting on a likert scale, 1 being "not at all confident" to 5 being "completely confident" for Periods 1 and 2.
Time Frame Days 0-21 following insertion of each IVR.
Hide Outcome Measure Data
Hide Analysis Population Description
Data was not collected for the third study period.
Arm/Group Title Period 1: TDF (Single IVR) Period 2: TDF-FTC (Dual IVR) Period 3: TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description:

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

Overall Number of Participants Analyzed 6 6 0
Mean (Full Range)
Unit of Measure: units on a scale
3.5
(1 to 5)
4
(1 to 5)
Time Frame Adverse event data was collected Days 0-21 following insertion of each IVR. Safety measures include: daily participant reports, colposcopy examinations, vaginal microbiome evaluations, or histology from vaginal biopsy.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title TDF (Single IVR) TDF-FTC (Dual IVR) TDF-FTC-MVC (Triple IVR)
Hide Arm/Group Description

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

TDF IVR

If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.

TDF-FTC IVR

If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.

TDF-FTC-MVC IVR

All-Cause Mortality
TDF (Single IVR) TDF-FTC (Dual IVR) TDF-FTC-MVC (Triple IVR)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/6 (0.00%)      0/6 (0.00%)      0/6 (0.00%)    
Hide Serious Adverse Events
TDF (Single IVR) TDF-FTC (Dual IVR) TDF-FTC-MVC (Triple IVR)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/6 (0.00%)      0/6 (0.00%)      0/6 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
TDF (Single IVR) TDF-FTC (Dual IVR) TDF-FTC-MVC (Triple IVR)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/6 (100.00%)      6/6 (100.00%)      4/6 (66.67%)    
Gastrointestinal disorders       
Diarrhea  [1]  1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0
General disorders       
Malaise  [2]  1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0
Nausea  [1]  0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1
Infections and infestations       
Candida (monilial vulvovaginitis)  [1]  0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1
Reproductive system and breast disorders       
Pelvic Pain  [1]  3/6 (50.00%)  5 2/6 (33.33%)  3 4/6 (66.67%)  5
Vaginal Discharge  [1]  3/6 (50.00%)  3 3/6 (50.00%)  3 1/6 (16.67%)  1
Metrorrhagia  [1]  1/6 (16.67%)  1 0/6 (0.00%)  0 2/6 (33.33%)  2
Vulvovaginal Itching  [1]  3/6 (50.00%)  3 0/6 (0.00%)  0 1/6 (16.67%)  1
Cervicovaginal Erythema  [1]  3/6 (50.00%)  3 1/6 (16.67%)  3 0/6 (0.00%)  0
Skin and subcutaneous tissue disorders       
Odor  [1]  0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1
Indicates events were collected by systematic assessment
[1]
Relationship: Possibly Related
[2]
Relationship: Not Related
The study’s main limitations include the small sample size, short duration (7 days), and the lack of FTC triphosphate measurements in vaginal tissue biopsies.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Sarjan Shah
Organization: Auritec Pharmaceuticals
Phone: 909-210-9715
EMail: sshah@auritecpharma.com
Layout table for additonal information
Responsible Party: Auritec Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02431273    
Other Study ID Numbers: ARV-IVR 01
2R44HD075636-02 ( U.S. NIH Grant/Contract )
First Submitted: August 4, 2014
First Posted: May 1, 2015
Results First Submitted: January 25, 2019
Results First Posted: July 2, 2019
Last Update Posted: July 2, 2019